Quaternised ammonium cyclodextrin compounds

ABSTRACT

Use of a compound of formula (I), wherein the symbol (a) represents a n-valent residue derived from a cyclodextrin compound by removing n of its hydroxyl groups; n is a number greater than 0 and represents the average number of substituents of formula (II) per molecule of said compound; h is 0 or 1; R 1  is a di-valent group selected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclic aralkylene, cycloalkylene and phenylene; R 2 , R 3  and R 4  are each independently of one another a group selected from alkyl, cycloalkyl, aryl, aralkyl and cycloheteryl; X m−  is a m-fold negatively charged anion; m is an integer being equal or greater than 1; and k is n/m in the preparation of an anti-infective medicament, as preservative and penetration enhancer.

The present invention relates to novel uses of quaternized ammoniumcyclodextrin compounds (hereinafter also QACD compounds) having theformula (I):

and to novel pharmaceutical, particularly ophthalmic compositionscomprising said compounds and their uses.

The compounds of formula (1), whereincyclodextrin

]_(n)represents a n-valent residue derived from a cyclodextrin (=CD) compoundby removing n of its hydroxyl groups;

-   n is a number greater than 0 and represents the average number of    substituents of formula-   per molecule of said compound;-   h is 0 or 1;-   R₁ is a di-valent group selected from alkylene, hydroxy alkylene,    halogeno alkylene, monocyclic aralkylene, cycloalkylene and    phenylene;-   R₂, R₃ and R₄ are each independently of one another a group selected    from alkyl, cycloalkyl, aryl, aralkyl, and cycloheteryl;-   X^(m−) is a m-fold negatively charged anion;-   m is an integer being equal or greater than 1; and-   k is n/m,    are known and described, for instance, in U.S. Pat. No. 3,453,257    (index h=1) or U.S. Pat. No. 5,241,059 (index h=0).

The compounds of formula (I) are described in said references as beingbetter soluble in water than non-cationic cyclodextrin compounds like,for example, beta-cyclodextrin itself. Based on these findings, U.S.Pat. No. 5,241,059 states in very general terms that compounds offormula (I) may be useful for making pharmaceuticals, for example. In amore recent investigation (T. Loftsson et al., Drug Development andIndustrial Pharmacy, 24(4), 365-370 (1998)) It has furthermore beenfound that cationic cyclodextrin derivatives like e.g.2-hydroxy-3-trimethyl-ammoniopropyl-beta-cyclodextrin, have a reducedsolubilizing effect on organic compounds in water in comparison touncharged cyclodextrins, like 2-hydroxypropyl-beta-cyclodextrin orrandomly methylated beta-cyclodextrin, in particular on zwitterioniccompounds, especially on the anti-inflammatory drug ETH-615 having thefollowing formula:

In a first aspect, the present invention is based on the surprisingfindings that the compounds of formula (I) are potent anti-microbialagents, in particular effective against bacteria and fungi. Furthermore,said compounds are also useful against viruses. The compounds of formula(I) exhibit a very low toxicity as shown, for example, by a LD₅₀ in miceof 750-1500 mg/kg) and exhibit excellent tolerability. Based on theiranti-microbial activity the compounds of formula (I) can be used, on oneside, as anti-infective drugs for the treatment of infective diseasescaused by the presence of bacteria, fungi or viruses and, on the otherside, as potent preservatives for all types of compositions whichrequire preservation, in particular pharmaceutical compositions.

Therefore, in a first aspect the instant invention relates to the use ofcompounds of the aforementioned formula (I) in the preparation of ananti-infective medicament, that means a medicament for the treatment ofbacterial, fungal and viral infections, in particular bacterial andfungal infections of a mammal, particularly a human, in need of suchtreatment.

The compounds of formula (I) represent a new class of anti-infectiveagents, and may therefore be particular valuable in view of controllinginfections of microorganisms, which are resistant against one or more ofanti-infective agents presently in use, like antibiotics. Furthermorethe new compounds may provide a further alternative for treatingpatients who cannot tolerate one or more known ant-infective compoundsor are allergic against the known compounds.

The compounds of formula (I) are substances derived from the well-knowncyclodextrins, a group of homologous oligosaccharides. As also wellknown, cyclodextrins are homologous cyclic molecules containing 6 ormore, especially 6, 7 or 8 alfa-D-glucopyranose units linked together atthe 1,4 positions as in amylose. When the number of alfa-D-glucopyranoseunits is 6, the molecule is known as an alfa-cyclodextrin, when thenumber of alfa-D-gluco-pyranose units is 7, the molecule is known as abeta-cyclodextrin; and when this number is 8, the molecule is known asgamma-cyclodextrin. For the purposes of this application the term“cyclodextrin” is intended to include the aforementioned forms, as wellas other corresponding cyclic molecules that have a still larger numberof alfa-D-glucopyranose units in the molecule, and, as well, mixtures ofthese and, optionally, other homologs. The various homologouscyclodextrins, having from six to eight units, or more, and theirmixtures, may be used as equivalent materials for the purposes of thisinvention. In practice, there may be little reason for separating thevarious fractions, and the cyclodextrin employed may contain apreponderance of specific cyclodextrin, e.g. beta-cyclodextrin. Nodistinction is intended between the various homologous cyclodextrins ortheir mixtures unless otherwise indicated, when using the term“cyclodextrin”.

The term quaternized ammonium cyclodextrin compound of the instantinvention also includes the corresponding derivatives wherein one ormore of the free hydroxyl groups have been etherified, in particularcorresponding methyl ether derivatives.

Preferred cyclodextrin compounds according to the invention include thecompounds of formula (Ia):

wherein X⁻ is a simple-charged anion and the other residues and h and nhave the meaning as in formula (I).

In formula (I) and (Ia) R₁ may be an alkylene, a hydroxy alkylene, anotherwise substituted alkylene, an aralkylene, a cycloalkylene, or aphenylene radical. Thus, R₁ may be, for instance, a branched or straightchain C₁-C₈alkylene, for Instance methylene, ethylene, a propylene,butylene, pentylene, hexylene or an octylene group etc. The foregoingand other alkylene radicals also may be substituted in one or moreplaces, for instance, by a hydroxyl, alkoxy, aryl or cycloalkyleneradical derived from, for example, cyclopropane, cyclobutane and higherhomologues. R₁ may also represent a phenylene radical which may besubstituted, if desired e.g. by alkoxy, alkyl, preferably C₁-C₄alkyl orhalogen.

R₂, R₃ and R₄ may be different or the same, and may be alkyl, aryl,aralkyl, cycloalkyl, cycloheteryl.

Thus, R₂, R₃ and R₄ may, for instance, be C₁-C₁₈alkyl, like methyl,ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, a branched orstraight chain pentyl, hexyl, heptyl, octyl, decyl or octadecyl and thelike alkyl radicals, and may also be substituted by one or moresubstituents, preferably one or more hydroxyl or halogen substituent.Preferably alkyl means C₁-C₁₀alkyl, for instance C₁-C₈alkyl, especiallyC₁-C₄alkyl, very specially methyl.

In the meaning cycloalkyl R₂, R₃ and R₄ may, preferably, representC₃-C₆cycloalkyl, like for example, cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl, which may also be substituted by one or more substiuents,e.g. by C₁-C₄alkyl, hydroxyl or halogen.

As aryl group R₂, R₃ and R₄, are preferably phenyl which may besubstituted, for instance by alkyl, in particular C₁-C₄alkyl, orhalogen.

In the meaning cycloheteryl R₂, R₃ and R₄ represent the residue of aheterocyclic group, for instance morpholinyl, pyridyl, pyrrolidyl,furfuryl, imidazolidyl, imidazolyl and the like.

X^(m−) is a m-fold negatively charged anion, preferably a halide,including bromide, chloride and iodide, nitrate, phosphate, sulfate,formate, acetate, butyrate, oleate, stearate, benzoate anion, or thelike, whereas [X⁻] is a simple-charged anion, preferably also oneselected from those above.

In preferred compounds of formula (I) or (Ia) R₂, R₃ and R₄ representsame or different C₁-C₁₈alkyl radicals. Specific preference is therebygiven to those alkyl radicals already mentioned above.

As is known, each cyclodextrin molecule of a compound of formula (I) or(Ia) may have a different degree of substitution. The total number ofquaternized ammonium groups In the molecule corresponding to the Indexn, may range from 1 to the maximum number of hydroxyl groups of the basecyclodextrin, that means theoretically up to 18 in case ofalfa-cyclodextrin, 21 in case of beta-cyclodextrin and 24 in case ofgamma-cyclodextrin. In a given quantity of a cyclodextrin derivative,there will however generally be some cyclodextrin molecules that are notsubstituted at all, together with other molecules that have differentnumbers of quaternized ammonium substituents. A statistical average istherefore employed to characterize the number of quaternized ammoniumgroups of the entire quantity of cyclodextrin (molecules). The presentinvention embraces QACD compounds of formula (I) or (Ia) having an indexn ranging from a value slightly above 0, for instance from about 0.1 tothe theoretical upper values indicated above. This necessarily impliesthat the QACD derivatives may be used in the form of a mixture withother materials, such as unreacted cyclodextrin, and, as well, insubstantially pure form. According to the art, the primary 6 positionhydroxyl groups in any anhydroglucose group appear to be the mostreactive, followed by the hydroxyl groups at the 2-position which arebelieved to be the next most reactive, and the hydroxyl at the3-position as the least reactive. Irrespective of the actual sequence ororder of reactions or the number of anhydroglucose units involved, theformulae (I) and (Ia) are intended to represent the QACD derivativeswherein the quaternized ammonium substitution may occur in differentdegrees of substitution at all or less than all anhydroglucose units inthe cyclodextrin. Preferably n ranges from about 1 to 8, more preferablyfrom about 1 to 4, for example from 1 to 3.

The QACD derivatives of formula (I) or (Ia), wherein the index h is 1,may, for instance, be prepared as described in detail in U.S. Pat. No.3,453.257 or analogically. The compounds of formulae (I) and (Ia),wherein the index h is 0, may, for example, be prepared as described inU.S. Pat. No. 5,241,059.

Specific embodiments of compounds useful for the instant inventioninclude the compounds of formula (Ia), wherein h is 1 and wherein R₁ isa branched or straight chain C₁-C₈alkylene or phenylene, which both maybe substituted In one or more places; R₂, R₃ and R₄ are different or thesame, and represent substituted or unsubstituted C₁-C₁₈alkyl;C₃-C₆cycloalkyl; phenyl; morpholinyl, pyridyl, pyrrolidyl, furfuryl,imidazolidyl or imidazolyl and X⁻ is a halide, nitrate, formate,acetate, butyrate, oleate, stearate, benzoate anion.

Particularly preferred is the use of compounds of formula (Ia), whereinR₁ is a branched or straight chain C₁-C₈alkylene, in particularC₁-C₄alkylene, more preferably ethylene or propylene, and R₂, R₃ and R₄are different or the same, and are substituted or unsubstitutedC₁-C₁₈alkyl, more particularly C₁-C₈alkyl, specifically C₁-C₄alkyl.

Preferred as well Is the use of the compounds of formula (I) or (Ia),wherein the symbolcyclodextrin

]_(n)represents a n-valent residue of alfa-, beta- or gamma-cyclodextrinincluding the corresponding partially or fully etherified compounds.

The instant invention furthermore relates to an ant-infectivepharmaceutical composition comprising an anti-microbially active drugselected from the compounds of formula (I) and particularly of formula(Ia) as described above.

Such pharmaceutical compositions according to the invention are suitablefor enteral, such as oral or rectal, parenteral, such as by intravenous,subcutaneous, intramuscular, or transdermal administration to mammalsincluding humans, and useful for the treatment of infective disordersresponsive thereto and comprise an anti-microbially effective amount ofa QACD compound of formula (I) or preferably of formula (Ia) as thepharmacologically active compound, alone or in combination, with one ormore pharmaceutically acceptable carriers and/or excipients suitable foreither enteral or parenteral application.

Such compositions may, for instance, be in the form of tablets orgelatin capsules and comprise, for instance, one or more of the QACDcompounds of formula (I) or (Ia) as active ingredient together with a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol; for tablets also c)binders e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and orpolyvinylpyrrolidone; if desired d) disintegrants, e.g. starches, agar,alginic acid or its sodium salt, or effervescent mixtures; and/or e)absorbants, colorants, flavors and sweeteners. Injectable compositionsaccording to the invention are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized, ifdesired, and contain adjuvants, such as stabilizing, wetting oremulsifying agents, salts for regulating the osmotic pressure and/orbuffers. If desired, such compositions may also comprise additionalpreserving and/or solubilizing agents, although this is usually notnecessary. Suitable formulations for transdermal application include aneffective amount of one or more QACD compound of formula (I) or (Ia)with a carrier. Advantageous carriers include absorbablepharmacologically acceptable solvents to assist passage through the skinof the host. Characteristically, transdermal devices are in the form ofa bandage comprising a backing member, a reservoir containing thecompound optionally with carriers, optionally a rate controlling barrierto deliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

Other forms of pharmaceutical compositions according to the inventioninclude inhalation formulations, emulsions, suspensions, rods, inserts,implants.

Suitable formulations for topical application, especially but notrestricted to the skin and the eyes, include aqueous solutions,ointments, creams or gels well-known in the art. Compositions accordingto the invention for topical use are particularly advantageous becausethe QACD compounds of formula (I) and (Ia) have unexpectedly been foundto exhibit, in addition to their anti-microbial effect, firstly anexcellent topical tolerability and secondly a particularly improvedpermeability through tissue like skin and especially ocular tissue, inparticular corneal and/or conjunctival tissue. Especially advantageousembodiments of the compositions according to the invention are thereforeophthalmic compositions comprising one or more compound of formula (I)or (Ia). Said compositions according to the Invention may also containother therapeutically valuable compounds and are generally preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1 to 75%, preferably about 1 to 50%,of the active ingredient.

In a further aspect the instant Invention relates to preservedpharmaceutical compositions comprising a preservative selected from thecompounds of formula (I), and in particular from compounds of formula(Ia) and additionally one or more pharmaceutically active, preferablyophthalmic drug other than a compound of said formula (I) and (Ia). Suchcompositions comprise the compounds of formula (I) or (Ia) inpreservatively effective amounts, for instance 0.01 to 10% based on thetotal weight of the composition, preferably 0.1 to 10%, e.g. 0.1 to 5%.If desired, said compositions may also comprise conventionalpreservatives in addition to the compounds of formulae (I) and (Ia),like for instance other quaternary ammonium compounds such asbenzalkonium chloride (N-benzyl-N—(C₈-C₁₈alkyl)-N,N-dimethylammoniumchloride), benzoxonium chloride or preservatives different fromquaternary ammonium salts like alkyl-mercury salts of thiosalicylicacid, such as, for example, thiomersal, phenylmercuric nitrate,phenylmercuric acetate or phenylmercuric borate, parabens, such as, forexample, methylparaben or propylparaben, alcohols, such as, for example,chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives,such as, for example, chlorohexidine or polyhexamethylene biguanide,sodium perborate, Germal®II or sorbic acid, in particular if thepreservative efficacy of such combinations is increased when compared tothe same amount of only one of the preservatives. A further specificembodiment of compositions according to the instant invention is free ofsuch conventional preservatives.

A further unexpected advantage of the QACD compounds of formula (I) and(Ia) is their compatibility with aqueous solutions of hyaluronic acidcompounds, in particular hyaluronic acid salts, e.g. sodium hyaluronate,which are a valuable and frequently used formulation component ofpharmaceutical, in particular of ophthalmic compositions, however, areknown to be incompatible with benzalkonium chloride, a very commonpreservative especially of ophthalmic compositions, together with whichthey irreversibly form a precipitate. The QACD compounds of formula (I)or formula (Ia) present an elegant way out of this dilemma because theyprovide an excellent preservative efficiacy like benzalkonium chloridein combination with a good compatibility with hyaluronic acidderivatives which are Incompatible with benzalkonium chloride.

As already mentioned above, the QACD compounds of formula (I) and (Ia)have furthermore proved to enhance the permeability of human or animaltissue, in particular of corresponding ocular and mucus tissue, forother drugs, specifically for drugs which form an inclusion complex withthe respective QACD compounds. In a further aspect the present Inventiontherefore relates to the use of compounds of formula (I) or (Ia) forenhancing the permeation of a drug through tissue and for enhancing thepenetration of a drug into tissue, wherein said drug is preferably adrug typically administered topical to said tissue, and, in still afurther aspect, to compositions comprising one or more pharmaceuticaldrug other than a compound of formula (I) or (Ia) and an enhancer forthe permeability of said drug through or into the human or animaltissue, in particular ocular or mucus tissue, which enhancer is selectedfrom the compounds of formula (I) and the compounds of formula (Ia) asdescribed above.

A specific embodiment of said compositions does not comprise azwitterionic drug in general, and/or specifically the drug ETH-615.described above.

Suitable drugs include but are not limited to anti-angiogenic drugs,anti-inflammatory drugs, anti-allergic drugs, anesthetic drugs, myopiapreventing/inhibiting drugs, miotics, carbonic anhydrase inhibitors,alpha blocking agents, antioxidants, vitamins, and biologic materialslike peptides, proteins, DNAS, RNAs and the like substances.

Specifically suitable drugs include furthermore ophthalmic and/orocularly tolerable, which may, for example, be selected from thefollowing drugs and combinations thereof:

-   -   anti-inflammatory drugs, such as steroids, e.g. dexamethasone,        fluorometholone, hydrocortisone, prednisolone; or so-called        non-steroidal anti-inflammatory drugs (NSAID) such as        COX-inhibitors, e.g. diclofenac, ketorolac, or indomethacin;    -   anti-allergic drugs, selected e.g. from FK506,        33-epi-chloro-33-desoxy-ascomycin, cromolyn, emadine, ketotifen,        levocabastine, iodoxamide, norketotifen, olopatadine, and        rizabene;    -   drugs to treat glaucoma (in particular intraocular pressure        treatment), selected e.g. from latanoprost, 15-keto-latanoprost,        unoprostone isopropyl, betaxolol, clonidine, levobunolol and        timolol;    -   anesthetic drugs, e.g. selected from cocaine hydrochloride,        lidocaine, oxybuprocaine and tetracaine hydrochloride;    -   myopia preventing/inhibiting drugs such as pirenzepine, atropine        and the like;    -   miotics, e.g. selected from carbachol, pilocarpine and        physostigmine;    -   carbonic anhydrase inhibitors, e.g. selected from acetazolamide        and dorzolamide;    -   alpha blocking agents, e.g. selected from apraclonidine and        brimonidine; and    -   antioxidants and/or vitamins, e.g. selected from ascorbic acid,        retinol, retinol acetate, retinol palmitate, and natural and        synthetic tocopherols, in particular alfa-tocopherol and alfa        tocopherol acetate; and    -   biologic materials like peptides, proteins, DNAs, RNAs and the        like substances, and if desired from    -   antifungal drugs, e.g. selected from amphotericin B, fluconazole        and natamycin; and    -   anti-viral drugs such as acyclovir, fomivirsen, ganciclovir, and        trifluridine.

The addressed drugs are specifically useful for the topical treatment ofa disease other than an infective disease, a fungus related disease, aviral disease, for example for the treatment of glaucoma, inflammation,allergy (such as hay fever), analgesia (e.g. surgery, mechanical ocularimpacts, etc.) and the like. Particularly preferred ophthalmic drugs aretherefore selected from anti-inflammatory drugs, anti-allergic drugs,and drugs to treat glaucoma.

It is known to those skilled in the art that a specific cyclodextrincompound does not automatically form an inclusion complex with anyrandomly chosen other compound, which may be desired. In such cases itis therefore preferred to use a QACD derivate derived from acyclodextrin compound, for instance alfa-, beta- or gamma-cyclodextrin,that meets the cavity needs of the other component or components, e.g.the pharmaceutical drug/drugs.

The amount of compounds of formula (I) or formula (Ia) present in suchan ophthalmic composition generally depends on the ophthalmic drug beingused is typically in the range of 0.01-35%, preferably from 0.5-25%,e.g. from 5-10%, 10-15% and 15-20%. Also preferred are amount from0.1-5% of the compound of formula (I) or (Ia), in particular 0.5-5% andmost particular 1-5% of said compound, by total weight of acorresponding ophthalmic composition.

The compositions for topical administration and/or ophthalmiccompositions comprise advantageously a carrier suitable for topicaladministration, such as for example water, mixtures of water andwater-miscible solvents, such as C₁-C₇-alkanols, vegetable oils ormineral oils comprising from 0.05 to 10%, preferably 0.5 to 5% by weighthydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, and othernon-toxic water-soluble polymers for ophthalmic uses, such as, forexample, cellulose derivatives, such as methylcellulose, alkali metalsalts of carboxymethylcellulose, hydroxymethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates ormethacrylates, such as salts of polyacrylic acid or ethyl acrylate,polyacrylamides, natural products, such as gelatin, alginates, pectins,tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia,starch derivatives, such as starch acetate and hydroxypropyl starch, andalso other synthetic products, such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid, such as neutral Carbopol, ormixtures of those polymers. Preferred carriers are water, cellulosederivatives, such as methylcellulose, alkali metal salts ofcarboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropylcellulose and hydroxypropylcellulose, neutralCarbopol, or mixtures thereof. Highly preferred is water. Theconcentration of the carrier is, for example, from 1 to 100000 times theconcentration of the active ingredient.

The ophthalmic compositions of the present invention may furthercomprise a tonicity enhancing agent. Tonicity enhancing agents are, forexample, ionic compounds, such as boric acid, or alkali metal oralkaline earth metal halides, such as, for example, CaCl₂, KBr, KCl,LiCl, Nal, NaBr or NaCl. Non-ionic tonicity enhancing agents are, forexample, urea, glycerol, sorbitol, mannitol, propylene glycol, ordextrose. For example, sufficient tonicity enhancing agent is added toimpart to the ready-for-use ophthalmic composition an osmolality ofapproximately from 50 to 1000 mOsmol, preferred from 100 to 400 mOsmol,more preferred from 200 to 400 mOsmol and even more preferred from 280to 350 mOsmol.

For the adjustment of the pH, preferably to a physiological pH, buffersmay especially be useful. Examples of buffer substances are acetate,ascorbate, borate, hydrogen carbonate/carbonate, citrate, gluconate,lactate, phosphate, propionate and TRIS (tromethamine) buffers.Tromethamine and borate buffer are preferred buffers. The amount ofbuffer substance added is, typically, that necessary to ensure andmaintain a physiologically tolerable pH range. The pH range is generallyin the range of from 4 to 9, preferably from 4.5 to 8.5 and morepreferably from 5.0 to 8.2.

Even though the compositions of the present Invention may furthercomprise an additional preservative, e.g on storage or to inhibitmicrobial growth after opening a closed container holding such acomposition and exposing such a composition to the air, this is normallynot necessary because of the ant-microbial effect of the QACD compoundsof formula (I) and (Ia). The term “anti-microbial effect” is meant toinclude an anti-bacterial, anti-fungal and anti-viral effect, inparticular an anti-bacterial and an anti-fungal effect.

A composition of the present invention may additionally require thepresence of a solubilizer, in particular if the active or the inactiveingredients tend to form a suspension or an emulsion.

A solubilizer suitable for compositions of the invention may, forexample, be selected from the group consisting of tyloxapol, fatty acidglycerol polyethylene glycol esters, fatty acid polyethylene glycolesters, polyethylene glycols, glycerol ethers, other cyclodextrincompounds (for example alpha-, beta- or gamma-cyclodextrin, e.g.alkylated, hydroxyalkylated, carboxyalkylated oralkyloxycarbonyl-alkylated derivatives, or mono- or diglycosyl-alfa-,-beta- or gamma-cyclodextrin, mono- or dimaltosyl-alfa-, -beta- or-gamma-cyclodextrin or panosyl-cyclodextrin), polysorbate 20,polysorbate 80 or mixtures of those compounds. A specific example of anespecially preferred solubilizer is a reaction product of castor oil andethylene oxide, for example the commercial products Cremophor EL® orCremophor RH 40®. Reaction products of castor oil and ethylene oxideappear to be particularly good solubilizers that are tolerated extremelywell by the eye. Another preferred solubilizer is selected fromtyloxapol and from a cyclodextrin. The concentration used dependsespecially on the concentration of the active ingredient. The amountadded is typically sufficient to solubilize the active ingredient. Forexample, the concentration of the solubilizer is typically from 0.1 to5000 times the concentration of the active Ingredient.

A composition of the invention may comprise further non-toxicexcipients, such as, for example, emulsifiers, wetting agents orfillers, such as, for example, polyethylene glycols, e.g. having anaverage molecular weight of 200, 300, 400 and 600, or higherpolyethylene glycols, such as Carbowax 1000, 1500, 4000, 6000 and 10000.Other excipients that may be used if desired are listed below but arenot intended to limit in any way the scope of the possible excipients.They are especially complexing agents, such as disodium-EDTA or EDTA,antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodiumhydrogen sulfite, butyl-hydroxyanisole, butyl-hydroxytoluene oralpha-tocopherol acetate; stabilizers, such thiourea, thiosorbitol,sodium dioctyl sulfosuccinate or monothioglycerol; or other excipients,such as, for example, lauric acid sorbitol ester, triethanol amineoleate or palmitic acid ester. Preferred exipients are complexingagents, such as disodium-EDTA. The amount and type of excipient added isin accordance with the particular requirements and is generally in therange of from approximately 0.0001 to approximately 90% by weight.

A further problem frequently arises when a drug is topicallyadministered, namely that it is often washed off again from the issue towhich it is applied during an unacceptably short time period.Compositions comprising one or more pharmaceutical drug, a compound offormula (I) or (Ia) as described hereinabove and a carrier comprising apolymer surprisingly provide a solution to this problem, too. It hasnamely been found that said compositions allow a sustained or prolongeddrug delivery at the place of administration.

Therefore the present invention includes a further aspect, the use of acomposition comprising one or more pharmaceutical drug, a compound offormula (I) or (Ia) and a carrier comprising a polymer as a drug dosagesystem for sustained delivery.

Compositions according to the instant invention which are especiallysuitable as a drug dosage system for sustained delivery are preferablyin a semi-solid (paste-like) or more preferably a solid state and are,for example, in the form of a film, a rod, a bar, a capsule, a cornealshield a corneal ring, an implant, an insert, an intraocular lens, atherapeutic contact lens, a tablet, e.g. a mini tablet, a mini-disc, ora pellet.

Carriers suitable for solid state medicaments representing a dosagesystem for sustained drug delivery according to the invention are forexample selected from

-   -   a matrix of a bioerodible polymer preferably being selected from        the group consisting of polyhydroxy-acids, such as polylactic        acid and polyglycolic acid; polyesters, polyorthoesters,        polyanhydrides, polycyanoacrylates, natural gums, such as acacia        gum and arabic gum; celluloses, such as carboxymethylcellulose;        methacrylate (co)polymers such as Eudragits, e.g. Eudragit RL        PO, Eudragit RS PO; and/or    -   a bioadhesive polymer preferably being selected from the group        consisting of maltodextrin, celluloses, such as carboxymethyl        cellulose, hydroxyethyl cellulose; chitosans; hyaluronic acid;        polyacrylates e.g. carbopol; polycarbophils e.g. Noveon AA-1;        polyvinylalcohol such as Mowiol 2688; polyvinylpyrrolidone such        as povidone K30.

Accordingly, the invention relates to a solid state medicament selectedfrom a film, a rod, a bar, a capsule, a corneal shield a corneal ring,an Implant, an insert, an intra-ocular lens, a therapeutic contact lens,a tablet, e.g. a mini tablet, a mini-disc, and a pellet comprising apharmaceutically effective drug, a compound of formula (I) or (Ia) and acarrier suitable for the manufacure of a solid state medicament. Saidsolid state medicaments provide in particular the synergistic advantageof sustained drug delivery with improved drug permeability.

The physical properties/appearances of a solid state medicamentaccording to the invention depends on the carriers used, and itsphysical appearance may, for example, range from soft to stiff, fromwater soluble up to water insoluble, from transparent to opaque and soon.

The concentration of an above carrier is, for example, from 1 to 100000times the concentration of the active ingredient.

An even more specific aspect of the instant invention is an ophthalmiccomposition comprising a QACD compound of formula (I) or (Ia), at leasta further pharmaceutically active component like an ophthalmic drugwhich is a novel drug delivery system providing the synergisticproperties of improved drug delivery, improved tolerability andexcellent preservative efficacy. Drug delivery as used herein refersparticularly to topical ocular administration.

Still further aspects of the instant invention are

-   -   a method for preserving a pharmaceutical composition comprising        adding to said pharmaceutical composition an effective amount of        a preservative selected from the compounds of formula (I);        preferably selected from the compounds of formula (Ia);    -   a method for enhancing the permeability of a drug contained in a        pharmaceutical composition through skin, buccal, mucosal,        pulmonal, vaginal or ocular, in particular conjunctival tissue,        more particularly for enhancing the permeability of a drug        contained in an ophthalmic composition through ocular tissue,        especially the corneal permeation, comprising adding to said        composition a compound selected from the compounds of formula        (I), preferably selected from the compounds of formula (Ia);    -   a method for synergistically enhancing the permeability of a        drug contained in a pharmaceutical composition through skin,        buccal, mucosal, pulmonal, vaginal or ocular, in particular        conjunctival tissue, more particularly for enhancing the        permeability of a drug contained in an ophthalmic composition        through ocular tissue, especially the corneal permeation, and        for preserving said composition comprising adding to said        composition a compound selected from the compounds of formula        (I), preferably selected from the compounds of formula (Ia); and    -   a method for controlled, in particular, sustained or prolonged        delivery of an organic compound, in particular a        pharmaceutically active drug at the place of administration,        comprising the following steps:        -   mixing said drug at least with a compound selected from the            compounds of formula (I) corresponding to claim 1, in            particular selected from the compounds of formula (Ia)            according to claim 2 and a polymer, in particular one or            more of a bioerodible polymer and/or one or more of a            bioadhesive polymer, and administering the composition            obtained thereby.

EXAMPLE 1 Increase of Corneal Permeation

Corneal Permeation Device:

The device used is a modified Valia-Chien system consisting of twowater-jacketed cells for temperature control. Each cell is filled withGBR buffer (see below), stirred by a magnet and continuously gassed withOxycarbon (5% CO₂/95% O₂). During an experiment, the cells are separatedby the cornea, one cell containing the test substance dissolved in GBRand acting as donor (tear side), the other one being the acceptor(aqueous humor side).

Corneas:

Pig eyes are obtained from the local abattoir. They are kept inDulbecco's MEM (minimal essential medium) with Glutamax-I (Gibco) on iceand used within a few hours after receipt.

Buffers:

Buffers for in vitro corneal permeation studies are adapted fromglutathione-bicarbonate-Ringer (GBR) solution. “GBR aqueous humor” isused in the acceptor cell and “GBR tears” on the donor side forequilibration. Their composition is listed in Table 1.

Assay of Corneal Permeation:

On receipt from the abattoir the eye is mounted on a dissection board,cornea facing up. After checking integrity of the cornea, the sclera isincised approximately 1-2 mm from the corneal rim with a scalpel and theanterior segment is excised. The iris and lens are carefully removedwith forceps without damaging the corneal structures. The cornea is thenmounted between the two cells of the permeation device with the help ofa pinch clamp. Immediately, 3 ml of previously warmed and gassed GBRbuffer are added to each cell, carefully removing any trapped airbubbles in the cells. The system is gassed and stirred for about 30minutes at 35° C. After equilibration, the donor side is emptied and thesame amount of a previously warmed formulation of active substance isadded at time t=0. An aliquot of 300 μl “GBR aqueous humor” is taken attime t=0 from the acceptor cell and the missing volume is replaced bythe same volume of fresh buffer. Subsequently, this procedure isrepeated in the acceptor cell at predefined time points and the aliquotsare analysed for active by HPLC. Both compartments are kept underconstant stirring with small magnets. The usual duration of anexperiment is 180 minutes which is also the time of contact of theformulation with the cornea. TABLE 1 Buffers used for in vitro cornealpermeation experiments GBR aqueous humor GBR tears ConstituentConcentration [mM] Concentration [mM] NaCl 95.75 115.75 NaH₂PO₄ 1.251.25 KCl 4 20 CaCl₂ 2 2 MgCl₂ 1 1 Adenosine 0.5 0.5 NaHCO₃ 23 23Glutathione reduced 0.3 0.3 Glucose 77.7 27.75 H₂O q.s. q.s. pH 7.3-7.4*7.3-7.4* Osmolality 297 mOsm/kg 311 mOsm/kg*when gassed with 5% CO₂/95% O₂A) Corneal permeation experiments with diclofenac formulations

1) Diclofenac sodium 0.1% without thiomersal (marketed Voltaren Ophthaformulation, SDU) Average permeated amount Time (min) (micro-gram) S.D.0 0 0 30 0 0 60 0 0 90 0.1970182 0.160121 120 0.5716975 0.385907 1801.6826328 0.78374

2) Diclofenac sodium 0.1% with 2% HP-gamma-cyclodextrin and without BACAverage permeated amount Time (min) (micro-gram) S.D. 0 0 0 30 0 0 600.2512672 0.237461 90 1.2153835 0.532895 120 2.2474393 0.707873 1806.4313489 1.643572

3) Diclofenac sodium 0.1% with 0.1% OA-beta-CD and without BAC Averagepermeated amount Time (min) (micro-gram) S.D. 0 0 0 30 0.263057 0.1553260 1.767697 1.093765 90 5.807919 1.235891 120 10.71147 2.608262 18020.08034 3.651529

-   BAC=benzalkonium chloride-   HP-gamma-cyclodextrin=hydroxypropyl-gamma-cyclodextrin-   QA-beta-CD=3-(trimethylammonio)-2-hydroxypropyl-beta-cyclodextrin    chloride

In the above experiments the efficacy in drug permeation an embodimentof this invention (QA-beta-CD [item 3]) can directly be compared withrespect to the prior art situation (HP-gamma-cyclodextrin; [item 2)]).

B) Corneal permeation experiments with 5-methyl-2-(2′chloro-6′-fluoroanilino)phenyl acetic acid (Compound B)

1) Compound B 0.1% without thiomersal (analogous to marketed VoltarenOphtha formulation, SDU) Average permeated amount Time (min)(micro-gram) S.D. 0 0 0 30 0 0 60 0.0840 0.1361 90 0.4359 0.2176 1200.8800 0.3568 180 2.0137 0.4391

2) Compound B 0.1% with 2% HP-gamma-cyclodextrin and without BAC Averagepermeated amount Time (min) (micro-gram) S.D. 0 0 0 30 0 0 60 0.94560.7494 90 3.6156 2.1221 120 5.5475 2.8703 180 10.4593 4.4961

3) Compound B 0.1% with 0.1% QA-beta-cyclodextrin and without BACAverage permeated amount Time (min) (micro-gram) S.D. 0 0 0 30 0 0 602.2883 1.4595 90 6.7793 2.8701 120 12.4568 2.7525 180 21.9144 5.1823

-   BAC=benzalkonium chloride-   HP-gamma-cyclodextrin=hydroxypropyl-gamma-cyclodextrin-   QA-beta-cyclodextrin=3-(trimethylammonio)-2-hydroxypropyl-beta-cyclodextrin    chloride, empiric formula: (C₆H_(10-n)O₅)₇(C₆ H₁₅ONCl)_(n) =2-5.

Again the efficacy in drug permeation of an embodiment of this invention(QA-beta-CD [item 3)]) can directly be compared with respect to theprior art situation (HP-gamma-cyclodextrin; [item 2)]), in theseexperiments.

EXAMPLE 2 Preservative Effectiveness Test

0.2 g of QA-beta-CD(QA-beta-CD=3-(trimethylammonio)-2-hydroxypropyl-beta-cyclodextrinchloride, empiric formula: (C₆H_(10-n)O₅)₇(C₆H₁₅ONCl)_(n) n=2-5. areadded to 170 ml water (nanopure). Then 10.10 g of Sorbitol and 0.2 g ofDisodium edetate are added and the pH is adjusted to a value of 7.0-7.4and water added to make up 200 ml of resulting solution. The solution isfiltered through a Corning bottle top filter unit 0.22 μm CA understerile conditions. The solution has a pH of 7.35 and an osmolality of307 mOsm/kg (270-330).

Samples of the solution are inoculated with Escherichia coli ATCC 8739;Pseudomonas aeruginosa ATCC 9027, Staphyloccocus aureus ATCC 6538;Candida albicans ATCC 10231 and Aspergillus niger ATCC 16404,respectively and assayed for presence/growth at the times given in Table2. TABLE 2 Escherichia Pseudomonas Staphyloccocus Candida Aspergilluscoli aeruginosa aureus albicans niger ATCC ATCC 8739 ATCC 9027 ATCC 6538ATCC 10231 16404 Inoculum 2.5 10⁶ 2.0 10⁶ 1.1 10⁶ 1.1 10⁶ 2.9 10⁵ Time 0h 2.5 10⁵ 2.2 10⁵ 1.5 10⁵ 1.4 10⁵ 1.1 10⁴ Time 6 h <10² <10² 5.4 10³ — —Time 24 h <10² <10² <10² — — Time 7 d <10² <10² <10² <10² 2.7 10³ Time14 d — — — <10²   2 10² Time 21 d — — — — — Time 28 d <10² <10² <10²<10²  2. 10²

The tested solution meets the requirements as defined as EuropeanPharmacopeia (Eur. Ph.) criteria A for ophthalmic preparations, e.g. asdescribed in Eur. Ph. Supplement 2001, Section 5.1.3, page 293 to 295.

EXAMPLE 3

Films able to act as ocular Insert are prepared and tested. Thecompositions of the films are disclosed in Table 3.

All preparations are made under magnetic stirring (400 rpm) and at roomtemperature. Firstly, the glycerol is dissolved In 5 ml of doubledistilled water or, alternatively, In 5 ml of aqueous phosphate buffer(pH=7) for the composition A and B. Then the Mowiol 26-88 is added tosaid water or said phosphate buffer comprising said glycerol untilcomplete dissolution. The D-mannitol or QA-beta-CD are dissolved in theresulting solution and after complete dissolution of these components,the polyvinylpyrrolidone is added to the mixture. At last, ketotifenhydrogenfumarate is added under stirring, and the resulting solutionsare then centrifuged (500×g, 25 min, 25° C.) in order to removeimpurities. All solutions were very clear.

The solutions are then cast in petri dishes and dried in a desiccator(containing phosphor pentoxyde) under vacuum (13 mbar). Upon drying, theresulting thin layer films are scored according the semi quantitativescale of Table 4. Two Individuals conducted said evaluation blindly andindependently.

Table 5 shows the mean value of the overall score (possible range 0 to9) of the thin layer films cast in the Petri dishes.

After drying, the preparations comprising Mowiol 26-88, glycerol andQA-beta-CD give excellent results. The maximum score is obtained for thebasic preparation loaded with QA-beta-CD (E). This score issignificantly higher than the one obtained when the preparation isloaded with D-mannitol (B). The resulting thin layer film is highlytransparent, easy to remove from the cast support and it exhibits aregular aspect and is essentially homogeneous. The addition ofpolyvinylpyrrolidone in the preparation is efficient and the resultingfilms exhibit good scores. This is particularly the case when thepreparations are loaded with QA-beta-CD (D).

Furthermore the compositions F to K are prepared, analogous to thecompositions A and D but loaded with different amounts of ketotifenhydrogen fumarate (Zaditen), namely 6.75, 12.5 and 20% respectively. Theresulting layers evidence good and equivalent scores with 6.75 and 12.5%of drug (F and I and G and J respectively). When the films are loadedwith 40 mg (20%) of Zaditen (H, K), the presence of some crystallinestructures is found in the film based on D-mannitol. Thisre-crystallization does not occur In presence of QA-beta-CD, probablybecause of a certain Interaction between the QACD component and thedrug.

Appropriate thin layer films are obtained with the addressedcompositions containing QA-beta-CD. TABLE 3 Thin layer film composition(in mg. per 200 mg film) Composition A B C D E F G H I J K Mowiol 26-88100 140 100 100 140 100 100 100 100 100 100 Hydroxypropyl cellulose 40Polyvinylpyrrolidone 40 — 40 — 40 40 40 40 40 40 D-mannitol 50 50 36.525 10 QA-beta-CD 50 50 50 36.5 25 10 Glycerin 10 10 10 10 10 10 10 10 1010 10 Ketotifen hydrogen fumarate 13.5 25 40 13.5 25 40

TABLE 4 Semi quantitative scale used to score the thin layer filmsCriterion Observation Score Thin layer film formed Yes 1 No 0Transparency Good 3 Average 2 Poor 1 None 0 Surface aspect Regular 1Non-regular 0 Homogeneity Yes 1 No 0 Remove from cast support Easy 3Average 2 Difficult 1 None 0

TABLE 5 Composition Macroscopic Score A 7.5 B 7.5 C 5.5 D 8 E 9 F 7.5 G8 H 8 I 7.5 J 8.5 K 9

1-33. (canceled)
 34. An anti-infective pharmaceutical compositioncomprising an antimicrobially active drug of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X^(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m. 35.The anti-infective composition according to claim 34, wherein the drugof formula (I) is a compound of formula (Ia)


36. The anti-infective composition according to claim 34, wherein thecomposition is topically administered to the skin or eye in the form ofan aqueous solution, ointment, cream or gel.
 37. A pharmaceuticalcomposition comprising a preservative, wherein the preservative is acompound of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

 per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X_(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m; andadditionally one or more pharmaceutically active drugs other than acompound of formula (I).
 38. The pharmaceutical composition according toclaim 37, wherein the preservative of formula (I) is a compound offormula (Ia)


39. The pharmaceutical composition according to claim 37, wherein theone or more pharmaceutically active drugs is an ophthalmic drug.
 40. Thepharmaceutical composition according to claim 37, wherein thepreservative is present in a concentration of 0.01 to 10% by weight ofthe total composition.
 41. An ophthalmic composition comprising one ormore ophthalmic drugs and an enhancer for the permeability of said drugthrough ocular tissue, wherein the drug is a compound of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X^(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m. 42.The ophthalmic composition of claim 41, wherein the compound of formula(I) is a compound of formula (Ia)


43. The ophthalmic composition according to claim 41, wherein the oculartissue is a corneal tissue.
 44. The ophthalmic composition according toclaim 41, wherein the enhancer is present in a concentration rangingfrom 0.01-35%.
 45. The ophthalmic composition according to claim 41,wherein the one or more ophthalmic drugs is selected from the groupconsisting of anti-inflammatory drugs, anti-allergic drugs, drugs totreat glaucoma, anesthetic drugs, myopia preventing/inhibiting drugs,miotics, carbonic anhydrase inhibitors, alpha blocking agents,antioxidants, vitamins and biologic materials.
 46. The ophthalmiccomposition according to claim 45, wherein the ophthalmic drug isselected from anti-inflammatory drugs, anti-allergic drugs, and drugs totreat glaucoma.
 47. The ophthalmic composition according to claim 41,further comprising one or more ophthalmically acceptable excipients. 48.The ophthalmic composition according to claim 47, wherein the excipientscomprise a salt of hyaluronic acid.
 49. The ophthalmic compositionaccording to claim 41, which is substantially free of benzalkoniumchloride.
 50. A drug dosage system for sustained delivery consistingessentially of a composition comprising one or more pharmaceuticallyactive drugs, a compound of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X^(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m, anda carrier comprising a polymer and selected from a film, a rod, a bar, acapsule, a corneal shield. a corneal ring, an implant, an insert, anintra-ocular lens, a therapeutic contact lens, a tablet, mini tablet, amini-disc, and a pellet.
 51. A method for preserving a pharmaceuticalcomposition, the method comprising: adding to said pharmaceuticalcomposition an effective amount of a preservative, wherein thepreservative is a compound of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X^(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m. 52.The method of claim 51, wherein the compound of formula (I) is acompound of formula (Ia)


53. A method for enhancing the permeability of a drug contained in apharmaceutical composition through skin, buccal, mucosal, pulmonal,vaginal or ocular tissue, the method comprising: adding to saidcomposition a compound of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X^(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m. 54.The method according to claim 53, wherein the compound of formula (I) isa compound of formula (Ia)


55. The method according to claim 53, wherein the ocular tissue isconjunctival or corneal tissue.
 56. A method for sustained or prolongeddelivery of a pharmaceutically active drug at the place ofadministration, comprising the following steps: mixing said drug atleast with a compound of formula (I)

wherein the symbolcyclodextrin

]_(n) represents a n-valent residue derived from a cyclodextrin compoundby removing n of its hydroxyl groups; n is a number greater than 0 andrepresents the average number of substituents of formula

per molecule of said compound; h is 0 or 1; R₁ is a di-valent groupselected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclicaralkylene, cycloalkylene and phenylene; R₂, R₃ and R₄ are eachindependently of one another a group selected from alkyl, cycloalkyl,aryl, aralkyl, and cycloheteryl; X^(m−) is a m-fold negatively chargedanion; m is an integer being equal or greater than 1; and k is n/m. anda polymer; and administering the composition obtained thereby.
 57. Themethod of claim 56, wherein the compound of formula (I) is a compound offormula (Ia)